System and method for managing detrimental cardiac remodeling

ABSTRACT

A system and method for managing and inhibiting cardiac remodeling in MI patients. Bi-ventricular stimulation is constantly provided with and without sensing to encourage normal pumping of the heart on a consistent basis. Pulses are administered using an anodal pulse followed by a cathodal pulse to stimulate cardiac muscle contraction. Stem cells are administered to MI areas to encourage regeneration of cardiac tissue in the damaged area. Stimulation may be provided to both healthy and compromised cardiac tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) fromprovisional application No. 60/575,121 filed May 28, 2004. The60/575,121 provisional application is incorporated by reference herein,in its entirety, for all purposes. This application is a continuation inpart of U.S. patent application Ser. No. 10/053,750 filed Jan. 21, 2002,pending, which is a continuation of U.S. patent application Ser. No.09/690,947, filed Oct. 18, 2000, now U.S. Pat. No. 6,341,235, which is acontinuation-in-part of U.S. patent application Ser. No. 09/008,636filed Jan. 16, 1998, now U.S. Pat. No. 6,136,019, which is acontinuation-in-part of U.S. patent application Ser. No. 08/699,552,filed Aug. 19, 1996, now U.S. Pat. No. 5,871,506 and a continuation inpart of U.S. patent application Ser. No. 10/754,887 filed Jan. 10, 2004now U.S. Pat. No. 7,203,537, pending, which is a continuation-in-part ofU.S. patent application Ser. No. 09/929,478 filed Aug. 14, 2001, nowU.S. Pat. No. 6,895,274, which is a continuation of U.S. Ser. No.09/231,570 application filed Jan. 14, 1999, now U.S. Pat. No. 6,295,470,which is a continuation-in-part of U.S. patent application Ser. No.08/699,552, filed Aug. 19, 1996, now U.S. Pat. No. 5,871,506. The Ser.Nos. 10/053,750, 09/690,947, 09/008,636, and 08/699,552 are allincorporated by reference herein, in their entirety, for all purposes.

BACKGROUND

This application is generally related to treatment of the heart, andmore particularly to managing and preventing detrimental cardiacremodeling following myocardial infarction. Remodeling of the heart is aharmful physical change in the heart that occurs with heart failure,heart attack, and heart disease. Remodeling is characterized byenlargement of the heart and thinning of the heart walls. For example,after a heart attack, while the normal heart muscle responds normally toexcitatory pulses, tissue that is damaged by the heart attack does notrespond or responds in a slower than normal rate to excitatory pulses.The healthy tissue however, continuing to function normally, placesincreased stress on the damaged and marginalized tissue, thereby“stretching” it. The stretching increases the volume of blood held bythe heart resulting in a short term increased blood output via aFrank-Sterling mechanism. In this way, the heart muscle behavessomething like a rubber band—the more it is stretched, the more “snap”the heart generates. However, if cardiac muscle is overstretched, or ifthe heart is stretched repetitively over a long period of time, iteventually loses its “snap” and becomes flaccid (a form of remodeling).Remodeling progresses in stages. Following a heart attack or as aconsequence of heart disease, the heart becomes rounder and larger.Heart muscle cells die and the heart as a pump gets weaker. If theremodeling is allowed to progress, the heart's main pumping chamber—theleft ventricle—enlarges and changes shape, getting rounder. The heartalso undergoes changes at the cell level.

The heart is divided into the right side and the left side. The rightside, comprising the right atrium and ventricle, collects and pumpsde-oxygenated blood to the lungs to pick up oxygen. The left side,comprising the left atrium and ventricle, collects and pumps oxygenatedblood to the body. Oxygen-poor blood returning from the body enters theright atrium through the vena cava. The right atrium contracts, pushingblood through the tricuspid valve and into the right ventricle. Theright ventricle contracts to pump blood through the pulmonic valve andinto the pulmonary artery, which connects to the lungs. The blood picksup oxygen in the lungs and then travels back to the heart through thepulmonary veins. The pulmonary veins empty into the left atrium, whichcontracts to push oxygenated blood into the left ventricle. The leftventricle contracts, pushing the blood through the aortic valve and intothe aorta, which connects to the rest of the body. Coronary arteriesextending from the aorta provide the heart blood.

The heart's own pacemaker is located in the atrium and is responsiblefor initiation of the heartbeat. The heartbeat begins with activation ofatrial tissue in the pacemaker region (i.e., the sinoatrial or “SA”node), followed by cell-to-cell spread of excitation throughout theatrium. The only normal link of excitable tissue connecting the atria tothe ventricles is the atrioventricular (AV) node located at the boundarybetween the atria and the ventricles. Propagation takes place at a slowvelocity, but at the ventricular end the bundle of His (i.e., theelectrical conduction pathway located in the ventricular septum) and thebundle braides carry the excitation to many sites in the right and leftventricle at a relatively high velocity of 1-2 m/s. The slow conductionin the AV junction results in a delay of around 0.1 seconds betweenatrial and ventricular excitation. This timing facilitates terminalfilling of the ventricles from atrial contraction prior to ventricularcontraction. After the slowing of the AV node, the bundle of Hisseparates into two bundle branches (left and right) propagating alongeach side of the septum. The bundles ramify into Purkinje fibers thatdiverge to the inner sides of the ventricular walls. This insures thepropagation of excitatory pulses within the ventricular conductionsystem proceeds at a relative high speed when compared to thepropagation through the AV node.

The syndrome of “heart failure” is a common course for the progressionof many forms of heart disease. Heart failure may be considered to bethe condition in which an abnormality of cardiac function is responsiblefor the inability of the heart to pump blood at a rate commensurate withthe requirements of the metabolizing tissues, or can do so only at anabnormally elevated filling pressure. Typically, the elevated fillingpressures result in dilatation of the left ventricular chamber.Etiologies that can lead to this form of failure include idiopathiccardiomyopathy, viral cardiomyopathy, and ischemic cardiomyopathy.

Heart failure is a chronic condition that affects over five millionAmericans, and is the most common reason for hospitalization amongelderly persons. Contrary to its name, heart failure is not a heartattack. Neither does the heart suddenly stop beating. Heart failuremeans that the heart is failing to pump enough blood to meet the body'sneeds. It often occurs in patients whose hearts have been weakened ordamaged by a heart attack or other conditions. As the heart continues tofail, patients may experience breathlessness, fluid build-up in thelimbs and severe fatigue. Delays in response of the septum to excitatorypulse may cause contractions that are not simultaneous and therefore theventricular contraction pattern is non-concentric. In this mode, theheart is beating inefficiently.

When the heart is working properly, both of its lower chambers(ventricles) pump at the same time and in sync with the pumping of thetwo upper chambers (atria). Up to 40 percent of heart failure patients,however, have disturbances in the conduction of electrical impulses tothe ventricles (e.g., bundle branch block or intraventricular conductiondelay). As a result, the left and right ventricles are activated atdifferent times. When this happens, the walls of the left ventricle (thechamber responsible for pumping blood throughout the body) do notcontract simultaneously, reducing the heart's efficiency as a pump. Theheart typically responds by beating faster and dilating. This results ina vicious cycle of further dilation, constriction of the vessels in thebody, salt and water retention, and further worsening of heart failure.These conduction delays do not respond to antiarrhythmics or otherdrugs.

Patients who have heart failure may be candidates to receive apacemaker. A biventricular pacemaker is a type of implantable pacemakerdesigned to treat heart failure. A biventricular pacemaker can helpsynchronize the lower chambers by sending electrical signalssimultaneously to the left ventricle and to the right ventricle. Bystimulating both ventricles (biventricular pacing), the pacemaker makesthe walls of the right and left ventricles pump together again. Theheart is thus resynchronized, pumping more efficiently while causingless wear and tear on the heart muscle itself. This is why biventricularpacing is also referred to as cardiac resynchronization therapy (CRT).

For patients who suffer from heart failure, remodeling of the heart mayoccur. Remodeling associated with heart failure is characterized byenlargement of the heart's left ventricle. In addition, the leftventricle walls become thinner. There is an increased use of oxygen,greater degree of mitral valve regurgitation, and decreased ejectionfraction. Remodeling sets off a “domino effect” of further damage toheart cells and more severe heart disease. Biventricular pacing of thepresent invention can potentially reverse the process. This beneficialeffect on the heart is called “reverse remodeling.” Typicalbiventricular pacemakers use cathodal pulses of 2.5 volts in the atriumand 5 volts in the ventricle.

Heart Attack

A heart attack is an event that results in pernanent heart damage ordeath. It is also known as a myocardial infarction, because part of theheart muscle (myocardium) may literally die (infarct). A heart attackoccurs when one of the coronary arteries becomes severely or totallyblocked, usually by a blood clot. When the heart muscle does not receivethe oxygenated blood that it needs, it will begin to die. The severityof a heart attack usually depends on how much of the heart muscle isinjured or dies during the heart attack.

Although a heart attack is usually the result of a number of chronicheart conditions (e.g., coronary artery disease), the trigger for aheart attack is often a blood clot that has blocked the flow of bloodthrough a coronary artery. If the artery has already been narrowed byfatty plaque (a disease called atherosclerosis), the blood clot may belarge enough to block the blood flow severely or completely. The victimmay experience an episode of cardiac ischemia, which is a condition inwhich the heart is not getting enough oxygenated blood. This is oftenaccompanied by angina (a type of chest pain, pressure or discomfort),although silent ischemia shows no signs at all. Severe or lengthyepisodes of cardiac ischemia can trigger a heart attack. Depending uponthe severity of both the attack and of the subsequent scarring, a heartattack can lead to the following:

-   -   Heart failure, a chronic condition in which at least one chamber        of the heart is not pumping well enough to meet the body's        demands.    -   Electrical instability of the heart, which can cause a        potentially dangerous abnormal heart rhythm (arrhythmia).    -   Cardiac arrest, in which the heart stops beating altogether,        resulting in sudden cardiac death in the absence of immediate        medical attention.    -   Cardiogenic shock, a condition in which damaged heart muscle        cannot pump normally and enters a shock-like state that is often        fatal.    -   Death.

Whether or not the heart muscle will continue to function after a heartattack depends on how much of it was damaged or how much of it diedbefore the patient could get medical treatment. The location of thedamage in the heart muscle is also important. Because different coronaryarteries supply different areas of the heart, the severity of the damagewill depend upon the degree to which the artery was blocked and theamount and area of the heart muscle that depended on that blockedartery.

As previously noted, tissue that is damaged by the heart attack does notrespond or responds at a slower than normal rate to excitatory pulses.The healthy tissue operates normally, but as a consequence placesincreased stress on this marginalized tissue, thereby “stretching” it.It is desirable to treat a heart attack so as to minimize the likelihoodof continued detrimental remodeling. This can be accomplished byreducing the contraction strength of healthy cardiac tissues, byincreasing the contraction strength of marginalized cardiac tissue, orby implementing a combination of both therapies.

Heart Disease and Arrhythmia

Disease affecting the AV junction may result in interference with normalAV conduction. This is described by different degrees of block. Infirst-degree block the effect is simply slowed conduction, insecond-degree block there is a periodic dropped beat, but inthird-degree block no signal reaches the ventricles. This lattercondition is also referred to as complete heart block. In this case theventricles are completely decoupled from the atria. Whereas the atrialheart rate is still determined at the AV node, the ventricles are pacedby ectopic ventricular sites. Since under normal conditions theventricles are driven by the atria, the latent ventricular pacemakersmust have a lower rate. Consequently, in complete heart block theventricles beat at a low rate (bradycardia). Even this condition may notrequire medical attention, but if the heart rate is too low, a conditionknown as Stokes-Adams syndrome, the situation becomes life-threatening.The prognosis in the case of complete heart block and Stokes-Adams is50% mortality within one year. In this case the implantation of anartificial pacemaker is mandatory.

Another condition, known as the sick sinus syndrome, is also one forwhich the artificial pacemaker is the treatment of choice. In theseconditions, the bradycardia results from the atrial rate beingabnormally low. Thus, even though the AV junction is normal, theventricles are driven at too low a rate.

A wide variety of arrhythmias can occur after acute myocardialinfarction. Supraventricular tachyarrhythmias, including sinustachycardia, atrial fibrillation, and atrial flutter, are relativelycommon and generally not life-threatening. Ventricular arrhythmias havea high incidence: premature ventricular beats occur in up to 90% ofpatients, ventricular tachycardias in up to 40% of patients, andventricular fibrillation in up to 5%. Ventricular fibrillation is mostcommon in the first 24 to 48 hours after myocardial infarction and islife-threatening. Although nonsustained ventricular tachycardia is ofprognostic significance in the postinfarction period, it is not certainif therapy will alter prognosis. Conduction abnormalities andbradyarrhythmias, also frequent complications of acute myocardialinfarction, require pacing therapy when symptomatic.

Temporary pacing is typically used first. If symptoms persist, apermanent pacemaker may be needed. A pacemaker is an artificial deviceto electrically assist in pacing the heart so that the heart may pumpblood more effectively. Implantable electronic devices have beendeveloped to treat both abnormally slow heart rates (bradycardias) andexcessively rapid heart rates (tachycardias). The job of the pacemakeris to maintain a safe heart rate by delivering to the pumping chambersappropriately timed electrical impulses that replace the heart's normalrhythmic pulses. The device designed to perform this life-sustainingrole consists of a power source the size of a silver dollar (containingthe battery), and control circuits, wires or “leads” that connect thepower source to the chambers of the heart. The leads are typicallyplaced in contact with the right atrium or the right ventricle, or both.They allow the pacemaker to sense and stimulate in various combinations,depending on where the pacing is required.

Absent a diagnosis of arrhythmia, anti-arrhythmic pacing is nottypically used as a treatment for myocardial infarction victims.

Whether a myocardial infarction leads to heart failure depends to alarge extent on how the remaining normal heart muscle behaves. Theprocess of ventricular dilatation (remodeling) is generally the resultof chronic volume overload or specific damage to the myocardium. In anormal heart that is exposed to long term increased cardiac outputrequirements, for example, that of an athlete, there is an adaptiveprocess of slight ventricular dilation and muscle myocyte hypertrophy.In this way, the heart fully compensates for the increased cardiacoutput requirements. With damage to the myocardium or chronic volumeoverload, however, there are increased requirements put on thecontracting myocardium to such a level that this compensated state isnever achieved and the heart continues to dilate.

The basic problem with a large dilated left ventricle is that there is asignificant increase in wall tension and/or stress both during diastolicfilling and during systolic contraction. In a normal heart, theadaptation (or remodeling) of muscle hypertrophy (thickening) andventricular dilatation maintain a fairly constant wall tension forsystolic contraction. However, in a failing heart, the ongoingdilatation is greater than the hypertrophy and the result is a risingwall tension requirement for systolic contraction. This is felt to be anongoing insult to the muscle myocyte resulting in further muscle damage.The increase in wall stress is also true for diastolic filling.Additionally, because of the lack of cardiac output, there is generallya rise in ventricular filling pressure from several physiologicmechanisms. Moreover, in diastole there are both a diameter increase anda pressure increase over normal, both contributing to higher wall stresslevels. The increase in diastolic wall stress is felt to be the primarycontributor to ongoing dilatation of the chamber.

Inadequate pumping of blood into the arterial system by the heart issometimes referred to as “forward failure,” with “backward failure”referring to the resulting elevated pressures in the lungs and systemicveins leading to congestion. Backward failure is the natural consequenceof forward failure as blood in the pulmonary and venous systems fails tobe pumped out. Forward failure can be caused by impaired contractilityof the ventricles or by an increased afterload (i.e., the forcesresisting ejection of blood) due to, for example, systemic hypertensionor valvular dysfunction. One physiological compensatory mechanism thatacts to increase cardiac output is due to backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the preload (i.e., the degree to which the ventricles arestretched by the volume of blood in the ventricles at the end ofdiastole). An increase in preload causes an increase in stroke volumeduring systole, a phenomena known as the Frank-Starling principle. Thus,heart failure can be at least partially compensated by this mechanismbut at the expense of possible pulmonary and/or systemic congestion.

When the ventricles are stretched due to the increased preload over aperiod of time, the ventricles become dilated. The enlargement of theventricular volume causes increased ventricular wall stress at a givensystolic pressure. Along with the increased pressure-volume work done bythe ventricle, this acts as a stimulus for hypertrophy of theventricular myocardium leading to alterations in cellular structure, aprocess referred to as ventricular remodeling.

Hypertrophy can increase systolic pressures but also decreases thecompliance of the ventricles and hence increases diastolic fillingpressure to result in even more congestion. It also has been shown thatthe sustained stresses causing hypertrophy may induce apoptosis (i.e.,programmed cell death) of cardiac muscle cells and eventual wallthinning which causes further deterioration in cardiac function. Thus,although ventricular dilation and hypertrophy may at first becompensatory and increase cardiac output, the process ultimately resultsin both systolic and diastolic dysfunction. It has been shown that theextent of ventricular remodeling is positively correlated with increasedmortality in CHF patients.

Over the past several years, numerous randomized clinical trials havebeen completed that show that two classes of drugs can significantlyimprove the overall survival of patients who have signs of impendingheart failure (either low left ventricular ejection fraction orincreased ventricular dilation). These drugs are the beta blockers andthe ACE inhibitors. Beta-blockers work by blocking the effect ofadrenaline on the heart, and have been noted to have numerous beneficialeffects in several types of heart disease. Beta blockers reduce the riskof angina in patients with coronary artery disease, significantlyimprove the survival of patients with heart failure, significantlyreduce the risk of sudden death in patients after heart attacks, andappear to delay or prevent the remodeling seen in the left ventricleafter heart attacks. However, patients with severe asthma or other lungdisease simply cannot safely take these drugs.

ACE inhibitors block angiotensin converting enzyme, and thereby producenumerous salutary effects on the cardiovascular system. This class ofdrugs significantly improves long-term survival among survivors of acutemyocardial infarction, and in addition reduces the incidence of heartfailure (apparently by preventing or delaying remodeling), recurrentheart attacks, stroke, and sudden death.

While the use of drugs may be beneficial, following a myocardialinfarction the undamaged area of the heart is still required to workharder and the tissue damaged by the infarction remains unhealed.

What would be truly useful is to provide alternative methods of treatingheart failure and post myocadial infarction conditions that will reduceor prevent adverse remodeling and allow damaged tissue to heal. Suchalternative methods would be provided in lieu of, or in concert with,conventional pharmaceutical therapies and with new tissue-regenerationtherapies.

SUMMARY

An embodiment of the present invention provides a method for treatingthe heart following a myocardial infarction (MI). Electrical stimulationis provided to selected portions of the heart without regard to whethera diagnosis of arrhythmia has been made. Stimulation may be in the formof excitatory or non-excitatory pulses using cathodal, anodal, andbiphasic waveforms. The portions of the heart selected for stimulationare determined selected based on the type of stimulation to beadministered and the extent of the damage sustained by the cardiactissue. In an exemplary embodiment, only healthy cardiac tissue isstimulated.

In an alternative exemplary embodiment of the present invention,marginalized heart tissue can also be stimulated so that the heart beatsin a more balanced fashion.

In an exemplary embodiment, biphasic, biventricular stimulation isdirected to undamaged areas of the heart to enhance the muscularcontraction of the healthy tissue thereby allowing the heart to achievenormal or near-normal functioning. The enhanced muscular contraction ofthe stimulated portion of the heart reduces uneven heart loading andprevents or reduces the adverse forms of remodeling of the heartfollowing a myocardial infarction. The biphasic, biventricularstimulation of the exemplary embodiment of the present inventioncomprises continuous application of both cathodal and anodal pulsessimultaneously to the right and left ventricles through electrodes thatcontact undamaged portions of the heart.

In an embodiment of the present invention, unlike pacing that is used tocontrol arrhythmias, the non-excitatory biphasic stimulation is notapplied to the heart in response to sensing a cardiac signal indicativeof an arrhythmia. Rather, the non-excitatory biphasic stimulation isapplied continuously to allow the heart to compensate for the cardiactissue affected by a MI while avoiding undesirable forms of remodeling.Optionally, the application of the biphasic stimulation is timed tocoincide with an initialization of a depolarization wave as determinedby cardiac sensors.

Additionally, the stimulation of the exemplary embodiment may becombined with stem cell implantation at sites where the cardiac tissuehas been damaged. The stem cell therapy regenerates damaged cardiactissue so that over time, the stimulation therapy may be terminated.

In this exemplary embodiment of the present invention, the prevention ofadverse remodeling stems from a number of mechanisms. The effect ofbi-ventricular pacing provides increased inotropic effect while at thesame time reducing oxygen demand and consumption by the heart, and byreducing and equalizing the wall tension, in effect reducing thetendency to stretch damaged areas of the heart. Also, the stimulus forstem cell implantation and proper orientation depends on proper walltension and electrical activity over the damaged area. These conditionsare properly established by this treatment. Additionally, the exposureof the damaged cardiac tissue to an electrical current can directly healdamaged areas. This is similar to the use of currents of proper polarityto heal other tissues such as fractures of bone and skin incisions.

As will be appreciated by those skilled in the art, the description ofexemplary embodiments is not limiting. While biphasic, bi-ventricularstimulation is described herein, other waveforms and stimulation sitesmay be employed to reduce the workload on the undamaged cardiac tissueand to thereby allow the heart to reverse or avoid the undesirableremodeling. Additionally, therapies may utilize excitatory ornon-excitatory pulses. As previously noted, tissue that is damaged bythe heart attack does not respond or responds at a slower than normalrate to excitatory pulses. The healthy tissue places increased stress onthis marginalized tissue, thereby “stretching” it. It is desirable totreat a heart attack so as to minimize the likelihood of continueddetrimental remodeling. This can be accomplished by reducing thecontraction strength of healthy cardiac tissues, by increasing thecontraction strength of marginalized cardiac tissue, or by implementinga combination of both therapies.

It is therefore an aspect of the present invention to promote thehealing of cardiac tissue affected by a MI.

It is another aspect of the present invention to increase cardiac outputof cardiac tissue not affected by a MI through more coordinated cardiaccontraction leading to greater stroke volume with less cardiac workrequired.

It is yet another aspect of the present invention to stimulatemarginalized areas of cardiac tissue so that they contract to someextent leading to more balanced operation of the heart post-MI.

It is still another aspect of the present invention to apply acombination of stimulation to tissue that is damaged and to tissue thatis undamaged by an MI to promote balanced functioning of cardiac tissuepost-MI.

It is still another aspect of the present invention to reduce theadverse forms of remodeling of the heart following an MI.

It is yet another aspect of the present invention to continuouslystimulate selection portions of the heart not affected by an MI usingstimulation pulses.

It is a further aspect of the present invention to promote the healingof cardiac tissue affected by a MI using stem cells.

It is another aspect of the present invention to maintain wall tensionin the heart at acceptable levels in patients suffering from heartdisease.

It is a further aspect of the present invention to promote normalizingof wall stresses thereby promoting the implantation of stem cells indamaged tissue.

These and other aspects of the present invention will be apparent fromthe general and detailed description that follows.

According to an embodiment of the present invention, an apparatus forminimizing cardiac remodeling of a non-arrhythmic patient comprises aheart stimulation device, a left ventricular electrode group, and aright ventricular electrode group. The left ventricular electrode groupcomprises LV electrodes attached to the left ventricle at increasingdistances from the AV node. The right ventricular electrode groupcomprises RV electrodes attached to the left ventricle at increasingdistances from the AV node. The heart stimulation device is adapted tostimulate healthy and compromised areas of cardiac tissue.

The heart stimulation device attaches to the LV and RV electrodes andgenerates a timing signal coincident with a refractory period. Inresponse to the timing signal, the heart stimulation device sends pulsesto the LV and RV electrodes sequenced such that an initial pulse arrivesat an LV electrode and at an RV electrode nearest the AV junction andsubsequent pulses arrive at an LR and at an RV electrode progressivelyfurther from the AV junction.

In an embodiment of the present invention, the pulse is excitatory. Inanother embodiment of the present invention, the pulse isnon-excitatory. In yet another embodiment of the present invention, thepulse is biphaisic.

According to an embodiment of the present invention, the biphasic pulsecomprises a first stimulation phase having a first phase polarity, afirst phase amplitude, a first phase shape, and a first phase duration,so as to precondition the myocardium to accept subsequent stimulation.The biphasic pulse further comprises a second stimulation phase having asecond phase polarity, a second phase amplitude that is larger inabsolute value than the first phase amplitude, a second phase shape, anda second phase duration. In an embodiment of the present invention, thefirst phase polarity is positive, and the second phase polarity isnegative. In yet another embodiment of the present invention, the firstphase amplitude is at a maximum subthreshold amplitude.

In an embodiment of the present invention, stem cells are deposited onthe cardiac tissue. In one embodiment of the present invention, the LVand RV electrodes are located so as to electrically stimulate thecompromised area of cardiac tissue on which stem cells have beendeposited. In an alternate embodiment of the present invention, the LVand RV electrodes are located so as to preclude electrical stimulationof the compromised area of cardiac tissue on which stem cells have beendeposited.

According to an embodiment of the present invention, an apparatus forminimizing cardiac remodeling of a non-arrhythmic patient comprises aheart stimulation device, a left ventricular electrode group, a rightventricular electrode group, and a sensor. The sensor senses excitationof a heart chamber.

The left ventricular electrode group comprises LV electrodes attached tothe left ventricle at increasing distances from the AV node. The rightventricular electrode group comprises RV electrodes attached to the leftventricle at increasing distances from the AV node. The heartstimulation device is adapted to stimulate healthy and compromised areasof cardiac tissue.

The heart stimulation device attaches to the LV and RV electrodes andthe sensor. In response to a signal from the sensor, the heartstimulation device sends pulses to the LV and RV electrodes sequencedsuch that an initial pulse arrives at an LV electrode and at an RVelectrode nearest the AV junction and subsequent pulses arrive at an LRand at an RV electrode progressively further from the AV junction.

In an embodiment of the present invention, the pulse is excitatory. Inanother embodiment of the present invention, the pulse isnon-excitatory. In yet another embodiment of the present invention, thepulse is biphaisic.

According to an embodiment of the present invention, the biphasic pulsecomprises a first stimulation phase having a first phase polarity, afirst phase amplitude, a first phase shape, and a first phase duration,so as to precondition the myocardium to accept subsequent stimulation.The biphasic pulse further comprises a second stimulation phase having asecond phase polarity, a second phase amplitude that is larger inabsolute value than the first phase amplitude, a second phase shape, anda second phase duration. In an embodiment of the present invention, thefirst phase polarity is positive, and the second phase polarity isnegative. In yet another embodiment of the present invention, the firstphase amplitude is at a maximum subthreshold amplitude.

In an embodiment of the present invention, stem cells are deposited onthe cardiac tissue. In one embodiment of the present invention, the LVand RV electrodes are located so as to electrically stimulate thecompromised area of cardiac tissue on which stem cells have beendeposited. In an alternate embodiment of the present invention, the LVand RV electrodes are located so as to preclude electrical stimulationof the compromised area of cardiac tissue on which stem cells have beendeposited.

An embodiment of the present invention provides a method for minimizingcardiac remodeling of a non-arrhythmic patient. Stem cells areadministered to a myocardial infarct (MI) area of a patient. Biphasicbi-ventricular stimulation is continuously administered to cardiactissue outside of the MI area.

According to an embodiment of the present invention, the biphasic pulsecomprises a first stimulation phase having a first phase polarity, afirst phase amplitude, a first phase shape, and a first phase duration,so as to precondition the myocardium to accept subsequent stimulation.The biphasic pulse further comprises a second stimulation phase having asecond phase polarity, a second phase amplitude that is larger inabsolute value than the first phase amplitude, a second phase shape, anda second phase duration. In an embodiment of the present invention, thefirst phase polarity is positive, and the second phase polarity isnegative. In yet another embodiment of the present invention, the firstphase amplitude is at a maximum subthreshold amplitude.

In an embodiment of the present invention, stem cells are deposited onthe cardiac tissue. In one embodiment of the present invention, the LVand RV electrodes are located so as to electrically stimulate thecompromised area of cardiac tissue on which stem cells have beendeposited. In an alternate embodiment of the present invention, the LVand RV electrodes are located so as to preclude electrical stimulationof the compromised area of cardiac tissue on which stem cells have beendeposited.

According to an embodiment of the present invention, an apparatus forminimizing cardiac remodeling of a non-arrhythmic patient comprises aheart stimulation device, a left ventricular electrode group, a rightventricular electrode group, and a sensor. The sensor senses excitationof a heart chamber.

The left ventricular electrode group comprises LV electrodes attached tothe left ventricle at increasing distances from the AV node. The rightventricular electrode group comprises RV electrodes attached to the leftventricle at increasing distances from the AV node. The heartstimulation device is adapted to stimulate healthy and compromised areasof cardiac tissue. A compromised area of the heart has stem cellsdeposited thereon.

The heart stimulation device attaches to the LV and RV electrodes andthe sensor. In response to a signal from the sensor, the heartstimulation device sends pulses to the LV and RV electrodes sequencedsuch that an initial pulse arrives at an LV electrode and at an RVelectrode nearest the AV junction and subsequent pulses arrive at an LVand at an RV electrode progressively further from the AV junction.

In an embodiment of the present invention, stem cells are deposited onthe cardiac tissue. In one embodiment of the present invention, the LVand RV electrodes are located so as to electrically stimulate thecompromised area of cardiac tissue on which stem cells have beendeposited. In an alternate embodiment of the present invention, the LVand RV electrodes are located so as to preclude electrical stimulationof the compromised area of cardiac tissue on which stem cells have beendeposited.

DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a heart with multiple ventricular electrodes that areconnected to external surfaces of the ventricles, and includes aseparate electrode set for each of the right and left ventriclesaccording to embodiments of the present invention.

FIG. 2 is a schematic representation of a leading anodal biphasicstimulation according to an embodiment of the present invention.

FIG. 3 is a schematic representation of a leading anodal stimulation oflow level and long duration, followed by cathodal stimulation accordingto an embodiment of the present invention.

FIG. 4 is a schematic representation of leading anodal stimulation oframped low level and long duration, followed by cathodal stimulationaccording to an embodiment of the present invention.

FIG. 5 is a schematic representation of leading anodal stimulation oflow level and short duration administered in a series, followed bycathodal stimulation according to an embodiment of the presentinvention.

DETAILED DESCRIPTION

An embodiment of the present invention provides a method for treatingthe heart following a myocardial infarction (MI). Electrical stimulationis provided to selected portions of the heart without regard to whethera diagnosis of any arrhythmia has been given. Stimulation may be in theform of excitatory or non-excitatory pulses using cathodal, anodal, andbiphasic waveforms. The portions of the heart selected for stimulationare selected based on the type of stimulation to be administered and theextent of the damage sustained by the cardiac tissue. In an exemplaryembodiment, only healthy cardiac tissue is stimulated.

In an exemplary embodiment of the present invention, biphasic,biventricular stimulation is directed to undamaged areas of the heart toenhance the muscular contraction of the healthy tissue thereby allowingthe heart to achieve normal or near-normal functioning. The enhancedmuscular contraction of the stimulated portion of the heart reducesheart loading and prevents or reduces the adverse forms of remodeling ofthe heart following a myocardial infarction. The biphasic, biventricularstimulation comprises continuous application of both cathodal and anodalpulses simultaneously to the right and left ventricles throughelectrodes that contact undamaged portions of the heart.

In an embodiment of the present invention, unlike pacing that is used tocontrol arrhythmias, the biphasic stimulation is not applied to theheart in response to sensing a cardiac signal indicative of anarrhythmia. Rather, the biphasic stimulation is applied continuously toallow the heart to compensate for the cardiac tissue affected by an MIwhile avoiding undesirable forms of remodeling. Optionally, theapplication of the biphasic stimulation is timed to coincide with thebeginning of a depolarization wave as determined by cardiac sensors.

Additionally, the biphasic stimulation of the exemplary embodiment iscombined with stem cell implantation at sites where the cardiac tissuehas been damaged. The stem cell therapy regenerates damaged cardiactissue so that over time, the biphasic stimulation therapy may beterminated.

Referring to FIG. 1, a diagram of the heart illustrates the fourchambers: right atrium (RA), left atrium (LA), right ventricle (RV), andleft ventricle (LV). Electrode lead 201, connected to RV electrode group201A comprising individual electrodes 202, 204, 206, 208 and 210, isshown with the individual electrodes connected to multiple points on theexternal surfaces of the right ventricle. Electrode lead 301, connectedto LV electrode group 301A comprising individual electrodes 302, 304,306, 308 and 310, is shown with the individual electrodes connected tomultiple points on the external surfaces of the left ventricle. While RVelectrode group 201A and LV electrode group 301A are illustrated withfive electrodes per group, this is not meant as a limitation. Othergroup sizes may be used without departing from the scope of the presentinvention.

In alternative embodiments, the locations of the individual electrodesin FIG. 1 (202, 204, 206, 208 and 210; and 302, 304, 306, 308 and 310)are selected to avoid stimulation of damaged cardiac tissue as, forexample, tissue damaged as a result of an MI.

In yet another embodiment of the present invention, pulses are appliedto the electrodes so as to mimic the normal physiological flow of thenormal ventricular depolarization wave. In this embodiment, the areasclosest to (or at) the A-V node are first stimulated during a givenbeat. In an embodiment of the present invention, atrial excitation issensed (P-Q interval) or ventricular excitation is sensed (QRS interval)and an external excitatory pulse is applied to the first electrode(after an appropriate delay) to coincide with the beginning of theventricular depolarization wave. Subsequent excitatory pulses aredirected to areas progressively further from the A-V node. Areasintermediate between these two extremes are appropriately stimulated ona scaled time basis that, again, mimics the normal intrinsic conductionpaths that facilitate the most efficient cardiac contraction. In anembodiment of the present invention, the pulses are applied to healthycardiac tissue that is unaffected by the MI, thereby allowing thedamaged tissue to heal and the stimulation voltage to be low.

This progressive stimulation embodiment requires specific knowledge ofthe placement of each electrode relative to each other electrode, aswell as the placement relative to the electrical conduction pathways inthe heart. Thus, it is appropriate to contemplate “classes” ofelectrodes, in which, for example, electrodes are identified orcategorized according to when they are fired. In a simplistic five tiersystem, e.g., the first tier electrodes are designated as the first tobe fired (i.e., the electrodes closest to the A-V node), followedsuccessively (and temporally progressively according to the normalconducting paths) by the second, third, fourth, and fifth tierelectrodes, where the fifth tier electrodes would be the last to befired, and whose locations on the ventricle(s) would correspond to thelast areas to be depolarized in the course of a normal ventricularcontraction/beat. An even simpler (i.e., two, three or four) tieredsystem may be used, or one more complex (i.e., one with greater thanfive tiers, or with any other basis of electrode placement, such as ahoneycomb-like array in a particular area with a known or suspectedpathology as to rhythmicity, reentry, conduction, contractility, etc.Furthermore, multiple electrodes within a given tier may be numbered orotherwise distinctly identified so that the practitioner may test anduse electrodes with respect to known locations in the heart, forexample, to anticipate and/or bypass an area of electrical blockage. Inthis embodiment, multiple, small electrodes are pulsed with excitatorypulses in a physiologic sequential fashion.

In still another embodiment of the present invention, the techniquedescribed above for stimulating the ventricles is applied to the atria.In this embodiment, electrodes are progressively placed from close tothe SA node (first to be fired) to close to the AV node (last to befired), mimicking the normal intrinsic conduction paths of the atria.

Bypassing an area of damaged tissue is also anticipated by the presentinvention, and can be effected by first identifying such areas, forexample, by determining myocardial resistance values between electrodes.Electrical pulses then are routed to those myocardial areas withappropriately low resistances, following as closely as possible thelines of conduction of the normal intrinsic conduction paths.Communication of, and control of, measurements of resistance betweenelectrodes, as well as developing a bypass protocol for a particularpatient, can be effected by an external computer. The external computercan communicate with the pacemaker by any convenient method, forexample, radiotelemetry, direct coupling (as by connecting to anexternal wire from the pacemaker to the surface of the skin of thepatient), etc.

FIGS. 2 through 5 depict a range of biphasic stimulation protocols.These protocols have been disclosed in U.S. Pat. No. 5,871,506 to Mower,which is herein incorporated by reference in its entirety.

FIG. 2 depicts biphasic electrical stimulation in which a firststimulation phase comprising anodal stimulus 202 is administered withamplitude 204 and duration 206. The first stimulation phase is followedimmediately by a second stimulation phase comprising cathodal stimulus208, which is of equal intensity and duration to those of anodalstimulus 202.

FIG. 3 depicts biphasic electrical stimulation wherein a firststimulation phase comprising low level, long duration anodal stimulation302 having amplitude 304 and duration 306 is administered. This firststimulation phase is immediately followed by a second stimulation phasecomprising cathodal stimulation 308 of conventional intensity andduration. In an alternative embodiment of the invention, anodalstimulation 302 is at maximum subthreshold amplitude. In yet anotheralternative embodiment of the invention, anodal stimulation 302 is lessthan three volts. In another alternative embodiment of the invention,anodal stimulation 302 is a duration of approximately two to eightmilliseconds. In yet another alternative embodiment of the invention,cathodal stimulation 308 is of a short duration. In another alternativeembodiment of the invention, cathodal stimulation 308 is approximately0.3 to 1.5 milliseconds. In yet another alternative embodiment of theinvention, cathodal stimulation 308 is of a high amplitude. In anotheralternative embodiment of the invention, cathodal stimulation 308 is inthe approximate range of three to twenty volts. In yet anotheralternative embodiment of the present invention, cathodal stimulation308 is of a duration less than 0.3 milliseconds and at a voltage greaterthan twenty volts. In another alternative embodiment, anodal stimulation302 is administered over 200 milliseconds post heart beat. In the mannerdisclosed by these embodiments, as well as those alterations andmodifications which may become obvious upon the reading of thisspecification, a maximum membrane potential without activation isachieved in the first phase of stimulation.

FIG. 4 depicts biphasic electrical stimulation wherein a firststimulation phase comprising anodal stimulation 402 is administered overperiod 404 with rising intensity level 406. The ramp of rising intensitylevel 406 may be linear or non-linear, and the slope may vary. Thisanodal stimulation is immediately followed by a second stimulation phasecomprising cathodal stimulation 408 of conventional intensity andduration. In an alternative embodiment of the invention, anodalstimulation 402 rises to a maximum subthreshold amplitude. In yetanother alternative embodiment of the invention, anodal stimulation 402rises to a maximum amplitude that is less than three volts. In anotheralternative embodiment of the invention, anodal stimulation 402 is of aduration of approximately two to eight milliseconds. In yet anotheralternative embodiment of the invention, cathodal stimulation 408 is ofa short duration. In another alternative embodiment of the invention,cathodal stimulation 408 is approximately 0.3 to 1.5 milliseconds. Inyet another alternative embodiment of the invention, cathodalstimulation 408 is of a high amplitude. In another alternativeembodiment of the invention, cathodal stimulation 408 is in theapproximate range of three to twenty volts. In yet another alternativeembodiment of the present invention, cathodal stimulation 408 is of aduration less than 0.3 milliseconds and at a voltage greater than twentyvolts. In another alternative embodiment, anodal stimulation 402 isadministered over 200 milliseconds post heart beat. In the mannerdisclosed by these embodiments as well as those alterations andmodifications which may become obvious upon the reading of thisspecification, a maximum membrane potential without activation isachieved in the first phase of stimulation.

FIG. 5 depicts biphasic electrical stimulation wherein a firststimulation phase comprising series 502 of anodal pulses is administeredat amplitude 504. In one embodiment rest period 506 is of equal durationto stimulation period 508 and is administered at baseline amplitude. Inan alternative embodiment, rest period 506 is of a differing durationthan stimulation period 508 and is administered at baseline amplitude.Rest period 506 occurs after each stimulation period 508 with theexception that a second stimulation phase comprising cathodalstimulation 510 of conventional intensity and duration immediatelyfollows the completion of series 502. In an alternative embodiment ofthe invention, the total charge transferred through series 502 of anodalstimulation is at the maximum subthreshold level. In yet anotheralternative embodiment of the invention, the first stimulation pulse ofseries 502 is administered over 200 milliseconds post heart beat. Inanother alternative embodiment of the invention, cathodal stimulation510 is of a short duration. In yet another alternative embodiment of theinvention, cathodal stimulation 510 is approximately 0.3 to 1.5milliseconds. In another alternative embodiment of the invention,cathodal stimulation 510 is of a high amplitude. In yet anotheralternative embodiment of the invention, cathodal stimulation 510 is inthe approximate range of three to twenty volts. In another alternativeembodiment of the invention, cathodal stimulation 510 is of a durationless than 0.3 milliseconds and at a voltage greater than twenty volts.The individual pulses of the series of pulses may be square waves, orthey may be of any other shape, for example, pulses which decay linearlyor curvilinearly from an initial subthreshold amplitude, to a loweramplitude.

In the biphasic stimulation protocol practiced by the present invention,the magnitude of the anodal phase does not exceed the maximumsubthreshold amplitude. The anodal phase serves to precondition thestimulated myocardium, thereby lowering the excitation threshold suchthat a cathodal stimulation of lesser intensity than normal will producedepolarization leading to contraction.

The pacing and subsequent normalizing of wall stresses promotes theimplantation of stem cells in damaged tissue, and guides their properorientation during the maturation of the cells.

The values of duration and amplitude will depend on factors such as theplacement/position of the particular electrode (including, e.g., whetherthe electrode is in purely muscle tissue versus in specializedconducting or pacemaking tissue), whether damaged/scarred tissue is inclose vicinity to the electrode, depth of the electrode within thetissue, local tissue resistance, presence or absence of any of a largerange of local pathologies, etc. Nonetheless, typical anodal phasedurations often fall within the range from about two milliseconds toabout eight milliseconds, whereas typical cathodal durations often fallwithin the range from about 0.3 milliseconds to about 1.5 milliseconds.Typical anodal phase amplitudes (most commonly at the maximumsubthreshold amplitude) often fall within the range from about 0.5 voltto 3.5 volts, compared to typical cathodal phase amplitudes from about 3volts to about 20 volts.

Because the heart is constantly stimulated, the pacing pulses areapplied without the need for demand sensing. Further, constantconsistent pacing diminishes stress on the heart.

In another embodiment of the present invention, the damaged tissue islocated and treated by inserting or applying donor or “stem” cells.Means for inserting and means for applying stem cells to damaged cardiactissue are described in U.S. Patent Application No. 60/429,954, entitled“Method and Apparatus for Cell and Electrical Therapy of Living Tissue,”a utility application for which was filed on Nov. 25, 2003, both ofwhich applications are incorporated herein in their entirety for allpurposes. In an embodiment of the present invention, the damaged tissueis treated and biventricular pacing pulsing is continuously applied tofunctioning portions of the heart. In one embodiment, the pacing sitesare chosen to assure that the tissue treated with stem cells is notelectrically stimulated. In an alternate embodiment, the pacing sitesare chosen so that the tissue treated with stem cells receiveselectrical stimulation pulses having an amplitude below that required toexcite the heart tissue.

A system and method for managing detrimental cardiac remodelingfollowing myocardial infarction have been disclosed. It will also beunderstood that the invention may be embodied in other specific formswithout departing from the scope of the invention disclosed and that theexamples and embodiments described herein are in all respectsillustrative and not restrictive. Those skilled in the art of thepresent invention will recognize that other embodiments using theconcepts described herein are also possible. Further, any reference toclaim elements in the singular, for example, using the articles “a,”“an,” or “the,” is not to be construed as limiting the element to thesingular.

1. An apparatus for minimizing cardiac remodeling of a non-arrhythmic patient comprising: a heart stimulation device adapted to stimulate cardiac tissue, wherein the cardiac tissue comprises healthy and compromised areas; a left ventricular electrode group, wherein the left ventricular electrode group comprises LV electrodes attached to the left ventricle at increasing distances from the AV node; and a right ventricular electrode group, wherein the right ventricular electrode group comprises RV electrodes attached to the left ventricle at increasing distances from the AV node, and wherein, the heart stimulation device is further adapted to: attach to the LV and RV electrodes; generate a timing signal coincident with a refractory period: and in response to the timing signal, send pulses to the LV and RV electrodes sequenced such that an initial pulse arrives at an LV electrode and at an RV electrode nearest the AV junction and subsequent pulses arrive at an LV and at an RV electrode progressively further from the AV junction.
 2. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient of claim 1, wherein the pulse is excitatory.
 3. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient of claim 1, wherein the pulse is non-excitatory.
 4. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 1, wherein a compromised area of cardiac tissue has stem cells deposited thereon.
 5. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 4, wherein the LV and RV electrodes are located so as to electrically stimulate the compromised area of cardiac tissue on which stem cells have been deposited.
 6. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 4, wherein the LV and RV electrodes are located so as to preclude electrical stimulation of the compromised area of cardiac tissue on which stem cells have been deposited.
 7. An apparatus for minimizing cardiac remodeling of a non-arrhythmic patient comprising: a heart stimulation device adapted to stimulate cardiac tissue, wherein the cardiac tissue comprises healthy and compromised areas; a left ventricular electrode group, wherein the left ventricular electrode group comprises LV electrodes attached to the left ventricle at increasing distances from the AV node; a right ventricular electrode group, wherein the right ventricular electrode group comprises RV electrodes attached to the left ventricle at increasing distances from the AV node; and a sensor, and wherein, the sensor is adapted to sense excitation of a heart chamber, and wherein, the heart stimulation device is further adapted to: attach to the LV and RV electrodes; attach to the sensor; and in response to a signal from the sensor, send pulses to the LV and RV electrodes sequenced such that an initial pulse arrives at an LV electrode and at an RV electrode nearest the AV junction and subsequent pulses arrive at an LV and at an RV electrode progressively further from the AV junction.
 8. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient of claim 7, wherein the pulse is excitatory.
 9. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient of claim 7, wherein the pulse is non-excitatory.
 10. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 7, wherein a compromised area of cardiac tissue has stem cells deposited thereon.
 11. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 10, wherein the LV and RV electrodes are located so as to electrically stimulate the compromised area of cardiac tissue on which stem cells have been deposited.
 12. The apparatus for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 10, wherein the LV and RV electrodes are located so as to preclude electrical stimulation of the compromised area of cardiac tissue on which stem cells have been deposited.
 13. A method for minimizing cardiac remodeling of a non-arrhythmic patient comprising: administering stem cells to a myocardial infarct (MI) area of a patient; continuously administering biphasic bi-ventricular stimulation to cardiac tissue outside of the MI area, wherein the biphasic stimulation comprises: a first stimulation phase having a first phase polarity, a first phase amplitude, a first phase shape, and a first phase duration, so as to precondition the myocardium to accept subsequent stimulation, and a second stimulation phase having a second phase polarity, a second phase amplitude that is larger in absolute value than the first phase amplitude, a second phase shape, and a second phase duration.
 14. The method for minimizing cardiac remodeling of a non-arrhythmic patient of claim 13 wherein the first phase polarity is positive, and the second phase polarity is negative.
 15. The method for minimizing cardiac remodeling of a non-arrhythmic patient of claim 13 wherein the first phase amplitude is at a maximum subthreshold amplitude.
 16. The method for minimizing cardiac remodeling of a non-arrhythmic patient of claim 13 wherein the biphasic stimulation is administered so as to electrically stimulate the MI area to which stem cells have been administered.
 17. The method for minimizing cardiac remodeling of a non-arrhythmic patient according to claim 13, wherein the biphasic stimulation is administered so as to preclude electrical stimulation of the MI area to which stem cells have been administered. 